Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells

Abstract

e Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H ؉ -ATPase. Notably, executive mechanisms of both TRAIL-and TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1 (PARP-1), and depletion of p38␣ increases the levels of both types of cell death. Moreover, we found differences in signaling between TNF-and TRAIL-mediated necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1 (UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis. Furthermore, we discovered indications of an altered involvement of mitochondrial components, since overexpression of the mitochondrial protein Bcl-2 protected Jurkat cells from TRAIL-and TNF-mediated necroptosis, and overexpression of Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore, TRAIL does not require receptor internalization and endosome-lysosome acidification to mediate necroptosis. Taken together, pathways described for TRAIL-mediated necroptosis and differences from those for TNF-mediated necroptosis might be unique targets to increase or modify necroptotic signaling and eliminate tumor cells more specifically in future anticancer approaches.

Intracellular pH Regulates TRAIL-Induced Apoptosis and Necroptosis in Endothelial Cells

“…Death in endothelial cells at an acidic pH relies on the function of RIPK1 and caspase-8 (Figures 2 and 3 ). PARP-1 also appears to be affected by the cellular microenvironment, playing a limited role in necroptosis at pH 7.4 [ 47 , 48 ], and evident in the low pH cell death observed here ( Figure 3 ) and others [ 32 ]. Given the distinct function of caspase-8 and influence of PARP-1, the precise nature of cell death we have observed at low pH which we have termed “acidonecrosis” does not fit well as classical necroptosis or apoptosis.…”

Disrupting mitochondrial Ca2+ homeostasis causes tumor-selective TRAIL sensitization through mitochondrial network abnormalities

“…TRAIL primarily triggers the extrinsic and intrinsic apoptotic pathways by binding to two death receptors (DRs), TRAIL receptor (TRAIL-R)1/DR4 and TRAIL-R2/DR5 (5,6). TRAIL has also been shown to trigger other cell death modalities including autophagy (7,8) and necroptosis (9,10) in some cancers. Different cancers including malignant melanoma (MM) and osteosarcoma (OS) cells are resistant to TRAIL-induced apoptosis (11)(12)(13)(14)(15).…”

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

“…The caspase-independent regulated necrosis called necroptosis can be induced in a pan-caspase inhibited environment by TRAIL and TNF. TRAIL-induced necroptosis is ATG5 dependent while TNF-dependent necroptosis is ATG5 and ATG16L1 dependent [36]. Together, these links indicate that analyzes of autophagy and autophagic markers in tissues can provide information not only about autophagic activity, but also on various modes of cell death.…”